Project Summary/Abstract Atopic dermatitis (AD) is a highly pruritic chronic episodic inflammatory skin disease that often presents between 3 and 6 months of age but may also present during later childhood or in adulthood. In the US, AD affects roughly 10-20% of all children of all races and ethnic groups. The prevalence of AD is increasing worldwide and it is a major public health burden. The majority of children with AD will also develop asthma and seasonal allergies. From the recent Global Burden of Disease study, AD was among the top 50 most prevalent diseases worldwide and it had the second highest disability rank of all non -malignant skin diseases. Many genes have been associated with the onset of AD. These genes are mostly associated with skin barrier changes (e.g. FLG) or immune dysregulation. Antigen-presenting cells (APC) are known to be involved in the initiation of the skin immune response. APC presentation of antigen to the immune system is guided by human leukocyte antigen (HLA) molecules, which are encoded within the major histocompatibility complex (MHC) located on chromosome 6. Six large population genetic studies of children with AD have been published and three of these studies demonstrated an association between the 6p21.3 cytoband (i.e. the MHC) region and AD. In a preliminary study, we have shown, for the first time, that specific variation of the HLA II DRB1 allele results in amino acid variations at position 9 (pocket 4), position 26 (pocket 4), and position 78 (pocket 4) that were marginally associated with the prevalence of AD and markedly associated with the persistence of AD. Importantly, unlike many other associations between HLA alleles and diseases (e.g., diabetes), the pathogenesis of AD is known to be associated with cutaneous inflammation and HLA II is known to be expressed on APCs that have an effect on the inflammatory cascade. We plan to focus on the HLA region of the genome using new technology to better understand the genetics of AD and the interplay between skin barrier dysfunction and immune dysregulation. This proposal has two goals. The first goal is to define HLA variation associated with the onset and persistence of AD. The second goal is to demonstrate that HLA variation is associated with immune dysregulation in those with AD.